The treatment of cancer often includes the use of DNA damaging drugs and/or other DNA damaging agents, such as ionizing radiation. These treatments can be non-specific and, particularly at high doses, toxic to normal, rapidly dividing cells. This often leads to various side effects in patients undergoing cancer treatment.
For example, bone marrow suppression, a severe reduction of blood cell production in bone marrow, is one such side effect. It is characterized by both myelosuppression (anemia, neutropenia, agranulocytosis and thrombocytopenia) and lymphopenia. Neutropenia is characterized by a selective decrease in the number of circulating neutrophils and an enhanced susceptibility to bacterial infections. Anemia, a reduction in the number of red blood cells or erythrocytes, the quantity of hemoglobin, or the volume of packed red blood cells (characterized by a determination of the hematocrit) affects approximately 67% of cancer patients undergoing chemotherapy in the United States. See BioWorld Today, page 4, Jul. 23, 2002. Thrombocytopenia is a reduction in platelet number with increased susceptibility to bleeding. Lymphopenia is a common side-effect of chemotherapy characterized by reductions in the numbers of circulating lymphocytes (also called T- and B-cells). Lymphopenic patients are predisposed to a number of types of infections.
Thus, the medical practitioner typically has to balance the efficacy of chemotherapeutic and radiotherapeutic techniques in destroying abnormal proliferative cells with associated cytotoxic effects on normal cells. Because of this, the therapeutic index of chemotherapy and radiotherapy techniques is narrowed, often resulting in incomplete tumor reduction, tumor recurrence, increasing tumor burden, and induction of chemotherapy and/or radiation resistant tumors.
Numerous methods have been designed in an effort to reduce normal tissue damage while still delivering effective therapeutic doses of DNA damaging agents. With regard to IR, these techniques include brachytherapy, fractionated and hyperfractionated dosing, complicated dose scheduling and delivery systems, and high voltage therapy with a linear accelerator. However, such techniques only attempt to strike a balance between the therapeutic and undesirable effects of the radiation, and full efficacy has not been achieved.
Small molecules have been used to reduce some of the side effects of certain chemotherapeutic compounds. For example, leukovorin has been used to mitigate the effects of methotrexate on bone marrow cells and on gastrointestinal mucosa cells. Amifostine has been used to reduce the incidence of neutropenia-related fever and mucositis in patients receiving alkylating or platinum-containing chemotherapeutics. Also, dexrazoxane has been used to provide cardioprotection from anthracycline anti-cancer compounds. Unfortunately, there is concern that many chemoprotectants, such as dexrazoxane and amifostine, can decrease the efficacy of chemotherapy given concomitantly.
Additional chemoprotectant therapies include the use of growth factors. Hematopoietic growth factors are available on the market as recombinant proteins. These proteins include granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) and their derivatives for the treatment of neutropenia, and erythropoietin (EPO) and its derivatives for the treatment of anemia. However, while growth factors can hasten recovery of some blood cell lineages, they do not treat suppression of platelets, macrophages, T-cells or B-cells.
The non-selective kinase inhibitor staurosporine has been shown to afford protection from DNA damaging agents in some cultured cell types. See Chen et al., J. Natl. Cancer Inst., 92, 1999-2008 (2000); and Ojeda et al., Int. J. Radiat. Biol., 61, 663-667 (1992). Staurosporine is a naturally occurring product and non-selective kinase inhibitor that binds most mammalian kinases with high affinity. See Karaman et al., Nat. Biotechnol., 26, 127-132 (2008). Staurosporine treatment can elicit an array of cellular responses including apoptosis, cell cycle arrest and cell cycle checkpoint compromise depending on cell type, drug concentration, and length of exposure. For example, staurosporine has been shown to sensitize cells to DNA damaging agents such as ionizing radiation and chemotherapy (see Bernhard et al., Int. J. Radiat. Biol., 69, 575-584 (1996); Teyssier et al., Bull. Cancer, 86, 345-357 (1999); Hallahan et al., Radiat. Res., 129, 345-350 (1992); Zhang et al., J. Neurooncol., 15, 1-7 (1993); Guo et al., Int. J. Radiat. Biol., 82, 97-109 (2006); Bucher and Britten, Br. J. Cancer, 98, 523-528 (2008); Laredo et al., Blood, 84, 229-237 (1994); Luo et al., Neoplasia, 3, 411-419 (2001); Wang et al., Yao Xue Xue Bao, 31, 411-415 (1996); Chen et al., J. Natl. Cancer Inst., 92, 1999-2008 (2000); and Hirose et al., Cancer Res., 61, 5843-5849 (2001)) through several claimed mechanisms including abrogation of a G2 checkpoint response. The mechanism whereby staurosporine treatment affords protection from DNA damaging agents in some cultured cell types is unclear, with a few possible mechanisms suggested including inhibition of protein kinase C or decreasing CDK4 protein levels. See Chen et al., J. Natl. Cancer Inst., 92, 1999-2008 (2000); and Ojeda et al., Int. J. Radiat. Biol., 61, 663-667 (1992). No effect of staurosporine has been shown on hematopoietic progenitors, nor has staurosporine use well after exposure to DNA damaging agents been shown to afford protection. Further, staurosporine's non-selective kinase inhibition has led to significant toxicities independent of its effects on the cell cycle (e.g. hyperglycemia) after in vivo administration to mammals and these toxicities have precluded its clinical use.
Accordingly, there is an ongoing need for practical methods to protect subjects who are scheduled to incur, are at risk for incurring, or who have already incurred, exposure to DNA damaging agents and/or events and methods of augmenting the efficacy of toxicity reducing agents. In addition, an ongoing need exists for methods and compositions for treating autoimmune diseases by blocking the proliferation of immune cells.